A Comparison of Mediators Released or Generated by IFN-γ-Treated Human Mast Cells Following Aggregation of FcγRI or FcεRI

Abstract

The high affinity receptor for IgG (FcγRI, CD64) is expressed on human mast cells, where it is up-regulated by IFN-γ and, thus, may allow mast cells to be recruited through IgG-dependent mechanisms in IFN-γ-rich tissue inflammation. However, the mediators produced by human mast cells after aggregation of FcγRI are incompletely described, and it is unknown whether these mediators are distinct from those produced after activation of human mast cells via FcεRI. Thus, we investigated the release of histamine and arachidonic acid metabolites and examined the chemokine and cytokine mRNA profiles of IFN-γ-treated cultured human mast cells after FcγRI or FcεRI aggregation. Aggregation of FcγRI resulted in histamine release and PGD2 and LTC4 generation. These responses were qualitatively indistinguishable from responses stimulated via FcεRI. Aggregation of FcεRI or FcγRI led to an induction or accumulation of 22 cytokine and chemokine mRNAs. Among them, seven cytokines (TNF-α, IL-1β, IL-5, IL-6, IL-13, IL-1R antagonist, and GM-CSF) were significantly up-regulated via aggregation of FcγRI compared with FcεRI. TNF-α mRNA data were confirmed by quantitative RT-PCR and ELISA. Furthermore, we confirmed histamine and TNF-α data using IFN-γ-treated purified human lung mast cells. Thus, aggregation of FcγRI on mast cells led to up-regulation and/or release of three important classes of mediators: biogenic amines, lipid mediators, and cytokines. Some cytokines, such as TNF-α, were released and generated to a greater degree after FcγRI aggregation, suggesting that selected biologic responses of mast cells may be preferentially generated through FcγRI in an IFN-γ-rich environment.

CD4+ T Cell-Specific Deletion of IL-4 Receptor α Prevents Ovalbumin-Induced Anaphylaxis by an IFN-γ-Dependent Mechanism

“…In vitro, Ag-specific IgG can cause human basophil/mast degranulation and release of mediators (29,30). The same mediators are released by both IgG-and IgE-mediated degranulation (30). Clinically, IgE-mediated and IgG-mediated reactions are virtually identical, and so whereas IgE-independent reactions used to be called anaphylactoid, both forms of the disease are now known as anaphylaxis (31).…”

“…In vitro, Ag-specific IgG can cause human basophil/mast degranulation and release of mediators (29,30). The same mediators are released by both IgG-and IgE-mediated degranulation (30).…”

About the role and underlying mechanisms of cofactors in anaphylaxis

“…Besides FceRI, basophils and mast cells also express activating FccR, which can promote degranulation (63). Indeed, FccRI-dependent degranulation of human mast cells mediated by antibodies of the IgG1 subclass is very similar to FceRI stimulation in regard to the amount and the pattern of released mediators (64,65). Thus, IgG production induced by 'infection' could also determine the outcome of anaphylaxis.…”

Identification of specific gene expression profiles in human mast cells mediated by Toll-like receptor 4 and FcϵRI

“…[4][5][6][7][8][9] However, it has become clear that rodent MCs are somewhat different from their human counterparts in terms of their sensitivity to some cytokines and drugs and their receptor expression profiles such as for Fc␥R. 3,[10][11][12][13] It is also observed that the level of IgE-dependent TNF-␣ production by human MCs is quite low compared to that by rodent MCs. 3,4,14 Therefore, it is now necessary to determine if human MCs express TLR4.…”

“…1 Among mediators, the production of Th2-type cytokines such as interleukin 5 (IL-5) and CC chemokines such as I-309 by human MCs is believed to be responsible for the initiation and maintenance of IgE-dependent allergic reactions. 2,3 Recent studies in animal models indicate that mouse MCs may play a protective role in host defense against bacteria through production of tumor necrosis factor ␣ (TNF-␣) as a result of mainly Toll-like receptor 4 (TLR4)-or CD48-mediated activation. [4][5][6][7][8][9] However, it has become clear that rodent MCs are somewhat different from their human counterparts in terms of their sensitivity to some cytokines and drugs and their receptor expression profiles such as for Fc␥R.…”